WO2008023810A1 - Ester méthylique de l'acide 2-(4-méthoxycarbonylméthylphénoxyméthyl) benzoïque et son procédé de fabrication - Google Patents

Ester méthylique de l'acide 2-(4-méthoxycarbonylméthylphénoxyméthyl) benzoïque et son procédé de fabrication Download PDF

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Publication number
WO2008023810A1
WO2008023810A1 PCT/JP2007/066500 JP2007066500W WO2008023810A1 WO 2008023810 A1 WO2008023810 A1 WO 2008023810A1 JP 2007066500 W JP2007066500 W JP 2007066500W WO 2008023810 A1 WO2008023810 A1 WO 2008023810A1
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WO
WIPO (PCT)
Prior art keywords
methyl
formula
methoxycarbonylmethylphenoxymethyl
producing
represented
Prior art date
Application number
PCT/JP2007/066500
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English (en)
Japanese (ja)
Inventor
Tadashi Katsura
Taketo Hayashi
Masahide Tanaka
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Sumitomo Chemical Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Chemical Company, Limited filed Critical Sumitomo Chemical Company, Limited
Priority to EP07792980A priority Critical patent/EP2058294B1/fr
Priority to ES07792980T priority patent/ES2399453T3/es
Publication of WO2008023810A1 publication Critical patent/WO2008023810A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to methyl 2- (4-methoxycarbonylmethylphenoxymethyl) benzoate and a method for producing the same.
  • olopatadine which is a pharmaceutical product useful as an antiallergic agent
  • a reaction step shown in the following scheme for producing olopatadine from dibenzoxepin acetic acid is disclosed in JP-A-6-96 09. .
  • Dibenzoxepin acetic acid is produced by subjecting 2_ (4-methoxycarbonylmethylphenoxymethyl) benzoic acid or its ethyl ester, which is produced from phthalide or 2-methylbenzoic acid, to a ring-closing reaction.
  • 2_ (4-methoxycarbonylmethylphenoxymethyl) benzoic acid or its ethyl ester, which is produced from phthalide or 2-methylbenzoic acid
  • the method for producing an ester of 2- (4-carboxymethylphenoxymethyl) benzoic acid described in JP-A-6-96099 is a method represented by the following scheme: 4-hydroxyphenylacetic acid A 1.6-fold molar amount of phthalide with respect to methyl is used, and the reaction is further performed at a high temperature of 150 ° C for 6 hours.
  • the present invention provides 2- (4-methoxycarbonylmethylphenoxymethyl) benzoate useful as an intermediate of a pharmaceutical, a production method thereof, and a production method of dibenzoxepin acetic acid as its use.
  • Step 1 A step of producing 2-chloromethylbenzoyl chloride by reacting phthalide with thiohytonyl,
  • a process for producing methyl 2-chloromethylbenzoate represented by:
  • 2- (4-carboxymethylphenoxymethyl) benzoic acid can be produced efficiently and inexpensively on an industrial scale, which is advantageous in producing dibenzoxepin acetic acid.
  • a series of reactions can be performed at a temperature of less than 140 ° C., which is advantageous for energy saving using steam heating.
  • Step 1 Process for producing 2_chloromethylbenzoyl chloride by reacting phthalide with chlorothionyl chloride
  • This step is carried out in accordance with the description in US Pat. No. 6,22,020, and is usually carried out in a solvent.
  • a solvent For example, by adding thionyl chloride to a solution obtained by dissolving phthalide in a suitable solvent under heating, the phthalide and the salt can be reacted.
  • the solvent include aromatic hydrocarbons such as xylene and toluene, and halogenated hydrocarbons such as chlorobenzene, and xylene is preferred.
  • an acid catalyst such as BF 3 —ether complex.
  • the amount used is preferably from 100 to 100 parts by weight with respect to 100 parts by weight of the phthalide.
  • the solution may contain a quaternary ammonium salt (for example, benzyltriethyl ammonium chloride, benzyl trimethyl ammonium chloride, tetraptyl ammonium bromide, etc.) to promote the reaction.
  • a quaternary ammonium salt for example, benzyltriethyl ammonium chloride, benzyl trimethyl ammonium chloride, tetraptyl ammonium bromide, etc.
  • the content is preferably about 0.1 to 0.2 mol per mol of phthalide.
  • the amount used is preferably in the range of about 0.1 to 0.2 mol per 1 mol of phthalide.
  • the amount of thionyl chloride used is preferably about 1 to 2 moles per mole of phthalide.
  • the temperature of the phthalide or its solution at the time of addition of thionyl chloride is preferably 80 to 130 ° C.
  • the excess salt and solvent are removed.
  • step 1 2-chloromethylbenzoyl chloride obtained in step 1 can be used for the reaction with methanol without purification.
  • methanol dropwise over a period of about 0.5 to 2 hours per mole of 2_chloromethylbenzoyl chloride.
  • Methanol is added dropwise to the 2-chloromethylbenzoyl chloride lid, and the mixture is stirred at 30 to 60 ° C for 0.5 to 1 hour.
  • Methanol can be diluted with an appropriate solvent and added dropwise.
  • 2-chloromethylbenzoyl chloride may be added dropwise to a mixture of methanol and a suitable solvent.
  • the solvent include aromatic hydrocarbons such as toluene and xylene, and halogenated hydrocarbons such as chlorobenzene. Toluene is preferable.
  • the amount of methanol used is preferably about 1 to 3 moles per mole of 2_chloromethylbenzoyl chloride.
  • reaction solution contains hydrogen chloride generated by the reaction
  • the reaction solution may be dropped into a predetermined amount of potassium carbonate aqueous solution at 0 to 50 ° C. After neutralization, the sample is washed with about 15 to 35% by weight of saline, and the organic layer is concentrated under reduced pressure to obtain 2-chloromethylbenzoate represented by the formula (2) as a residue. Obtainable.
  • methyl 2-chloromethylbenzoate obtained in step 1 can be used for the next reaction without purification.
  • methyl 4-hydroxyphenylacetate can be obtained by reacting 4-hydroxyquinphenylacetic acid with methanol in the presence of an acid catalyst such as sulfuric acid, hydrochloric acid or phosphoric acid.
  • This step is usually performed in a solvent in the presence of a base under heating conditions of about 50 to 120 ° C.
  • a base examples include alkaline metal carbonates such as carbonated lithium and sodium carbonate, and alkaline metal hydroxides such as hydroxide hydroxide and sodium hydroxide.
  • Solvents include: Examples thereof include acid amides such as dimethylacetamide, aromatic hydrocarbons such as toluene, and halogenated hydrocarbons such as chlorobenzene.
  • 2-hydroxymethyl benzoate, potassium carbonate and a solvent are mixed and heated to 50 to 120 ° C. to a solution of 4-hydroxyphenylacetic acid. It can be carried out by adding methyl and stirring at the same temperature for about 1 to 12 hours.
  • Potassium carbonate is usually used at a ratio of about 0.5 to 1.5 moles per mole of methyl 2-chloromethylbenzoate
  • the solvent is usually 100 parts by weight of methyl 4-hydroxyphenylacetate. Is used at a ratio of about 100 to 500 parts by weight.
  • 4-Hydroxyphenyl acylacetate is used in moles approximately equal to methyl 2-chloromethylbenzoate, e.g.
  • 4-hydroxyphenylacetate methyl acetate is used in advance as potassium carbonate, sodium carbonate, etc. It reacts with bases such as alkali metal hydroxides such as alkaline metal carbonates, hydroxide hydroxide and sodium hydroxide, to lead to potassium salts, sodium salts, etc., and 2 _ methyl methyl chloromethylbenzoate and 4 It can also be reacted with the salt of hydroxyfuel methyl acetate.
  • the target product may be separated by an ordinary method.
  • the reaction solution is poured into water, an organic solvent (for example, toluene) is added, the organic layer is separated, washed with water, and the organic solvent is distilled off to obtain the target formula (1).
  • 2_ (4-Methoxycarbonylmethylphenoxymethyl) represented by methyl benzoate is obtained.
  • 2- (4-Carboxymethylphenoxymethyl) benzoic acid represented by the formula (5) can be produced by cyclization of the benzoic acid.
  • the dibenzoxepin acetic acid represented by this can be manufactured.
  • 2- (4-methoxycarbonylmethylphenoxymethyl) methyl benzoate is dissolved in an alcohol solvent such as methanol or ethanol, and a basic aqueous solution such as lithium hydroxide or sodium hydroxide, or hydrochloric acid or sulfuric acid. Treat with acidic aqueous solution.
  • the base or acid used is usually 1 mole to a large excess, preferably 1 mole to 5 moles per mole of 2- (4-methoxycarbonylmethylphenoxymethyl) methyl benzoate.
  • the reaction temperature is usually about 20 to 80 ° C.
  • the cyclization reaction of 2- (4-carboxymethylphenoxymethyl) benzoic acid may be performed under the conditions of a normal dehydration condensation reaction.
  • the cyclization reaction can be carried out by reacting 2- (4-carboxymethylphenoxymethyl) benzoic acid with a dehydrating agent such as trifluoroacetic anhydride, polyphosphoric acid, pentylic acid hydrin or the like.
  • a dehydrating agent such as trifluoroacetic anhydride, polyphosphoric acid, pentylic acid hydrin or the like.
  • a solvent such as a halogenated hydrocarbon such as chlorbenzene is usually used, and a catalyst such as a BF 3 -ether complex is preferably used.
  • the reaction temperature is usually about 20 to 50 ° C.
  • Example 2 The whole amount of 2- (4-methoxycarbonylmethylphenoxymethyl) benzoate obtained in Example 1 was charged into a four-necked flask, and 17.0 g of sodium hydroxide was added to 10 0 Om 1 of water. Add the dissolved solution and methanol 15 Om 1 at 65 ° C.
  • the present invention provides 2- (4-methoxycarbonylmethylphenoxymethyl) benzoate useful as an intermediate of a pharmaceutical, a production method thereof, and a production method of dibenzoxepin acetic acid as its use.
  • This dibenzoxepin acetic acid can be used to produce olopatadine, a drug useful as an antiallergic agent.

Abstract

L'invention concerne un procédé de fabrication de l'ester méthylique de l'acide 2-(4-méthoxycarbonylméthylphénoxyméthyl)benzoïque par réaction de l'ester méthylique de l'acide 2-chlorométhylbenzoïque et de l'ester méthylique de l'acide 4-hydroxyphénylacétique. Un acide dibenzooxépinacétique utile comme intermédiaire pour des produits pharmaceutiques peut être avantageusement obtenu par ce procédé de fabrication de l'ester méthylique de l'acide 2-(4-méthoxycarbonylméthylphénoxyméthyl)benzoïque.
PCT/JP2007/066500 2006-08-21 2007-08-20 Ester méthylique de l'acide 2-(4-méthoxycarbonylméthylphénoxyméthyl) benzoïque et son procédé de fabrication WO2008023810A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP07792980A EP2058294B1 (fr) 2006-08-21 2007-08-20 Procédé de fabrication d'ester méthylique de l'acide 2-(4-méthoxycarbonylméthylphénoxyméthyl) benzoïque
ES07792980T ES2399453T3 (es) 2006-08-21 2007-08-20 Método para producir éster metílico del ácido 2-(4-toxicarbonilmetilfenoximetil)benzoico

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006-224166 2006-08-21
JP2006224166 2006-08-21

Publications (1)

Publication Number Publication Date
WO2008023810A1 true WO2008023810A1 (fr) 2008-02-28

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PCT/JP2007/066500 WO2008023810A1 (fr) 2006-08-21 2007-08-20 Ester méthylique de l'acide 2-(4-méthoxycarbonylméthylphénoxyméthyl) benzoïque et son procédé de fabrication

Country Status (4)

Country Link
EP (1) EP2058294B1 (fr)
CN (1) CN101506141A (fr)
ES (1) ES2399453T3 (fr)
WO (1) WO2008023810A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102757339A (zh) * 2012-08-01 2012-10-31 北京联本医药化学技术有限公司 一种改进的4-(2-羧基苄氧基)苯乙酸制备方法
US11363815B2 (en) 2018-06-05 2022-06-21 Shenyang University Of Chemical Technology Trifluoroethyl thioether (sulfoxide) substituted benzene compound and use thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262318B (zh) * 2014-09-03 2016-02-17 河北仁合益康药业有限公司 一种盐酸奥洛他定的制备方法
CN106478503A (zh) * 2016-09-29 2017-03-08 上海勋和医药科技有限公司 Roxadustat中间体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5058084A (fr) * 1973-09-06 1975-05-20
DE2716230A1 (de) * 1976-03-17 1977-10-27 Hoechst Ag Medikament zur behandlung von hautentzuendungen
US4082850A (en) 1976-04-16 1978-04-04 American Hoechst Corporation Method of treating dermal inflammations
JPH069609A (ja) 1987-02-27 1994-01-18 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体
US6222060B1 (en) 1997-09-30 2001-04-24 Korean Research Institute Of Chemical Technology Process for preparing o-(carboalkoxy)phenylmethanesulfonyl chloride derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5058084A (fr) * 1973-09-06 1975-05-20
DE2716230A1 (de) * 1976-03-17 1977-10-27 Hoechst Ag Medikament zur behandlung von hautentzuendungen
US4082850A (en) 1976-04-16 1978-04-04 American Hoechst Corporation Method of treating dermal inflammations
JPH069609A (ja) 1987-02-27 1994-01-18 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体
US6222060B1 (en) 1997-09-30 2001-04-24 Korean Research Institute Of Chemical Technology Process for preparing o-(carboalkoxy)phenylmethanesulfonyl chloride derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2058294A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102757339A (zh) * 2012-08-01 2012-10-31 北京联本医药化学技术有限公司 一种改进的4-(2-羧基苄氧基)苯乙酸制备方法
US11363815B2 (en) 2018-06-05 2022-06-21 Shenyang University Of Chemical Technology Trifluoroethyl thioether (sulfoxide) substituted benzene compound and use thereof

Also Published As

Publication number Publication date
ES2399453T3 (es) 2013-04-01
EP2058294A1 (fr) 2009-05-13
EP2058294A4 (fr) 2010-11-17
CN101506141A (zh) 2009-08-12
EP2058294B1 (fr) 2013-01-02

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